HRP20040783A2 - Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazole-2-one for producing medicaments that inhibit pancreatic lipase - Google Patents

Description

The invention relates to the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones for the production of drugs that exhibit an inhibitory effect on pancreatic lipase, PL.

Substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones with an inhibitory effect on hormone-sensitive lipase are known from WO 01/17981 (HMR 1999/L 052) and WO 01/66531 (AVE-D 2000/A 015K).

It has now surprisingly been found that substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones exhibit an inhibitory effect on pancreatic lipase.

The subject of the invention is therefore the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones of the general formula 1,

[image]

where

R1 represents C1-C6-alkyl, C3-C9-cycloalkyl, whereby both groups can be mono- or multi-substituted with phenyl, C1-C4-alkyloxy, S-C1-C4-alkyl, N(C1-C4-alkyl)2 , and phenyl, on the other hand, can be singly or multiply substituted with halogen, C1-C4-alkyl, C1-C4-alkyloxy, nitro, CF3; and

R 2 , R 3 , R 4 and R 5 independently represent hydrogen, halogen, nitro, C 1 -C 4 -alkyl;

C1-C9-alkyloxy, which is substituted with fluorine, C6-C10-aryl, amino or with C1-C4-alkyl-amino;

C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C6-C10-aryloxy-C1-C4-alkyl, C3-C8-cycloalkyl or o-C3-C8-cycloalkyl, which may be mono-, di- or tri-substituted with halogen, CF3, C1-C4-alkyloxy or C1-C4-alkyl;

SO2-NH-C1-C6-alkyl, optionally substituted with N(C1-C6-alkyl)2, SO2-NH-(2,2,6,6,-tetramethylpiperidin-4-yl), SO2-NH-C1 -C6-cycloalkyl, if necessary singly or multiply substituted with C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or COX,

2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7,

provided that R 2 , R 3 , R 4 and R 5 are not simultaneously hydrogen, and

X can be O-C1-C6-alkyl, NH-C1-C6-alkyl, NH-C3-C8-cycloalkyl or N(C1-C6-alkyl)2 and N(C1-C6-alkyl)2 and also pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which may optionally be substituted with C1-C4-alkyl, benzyl, C6-C10-aryl, CO-C1-C4-alkyl, CO-C6-C10-aryl, CO-O-C1 -C4-alkyl, SO2-C1-C4-alkyl or

R 6 is hydrogen, C 1 -C 4 -alkyl or C 6 -C 10 -aryl-C 1 -C 4 -alkyl, wherein the aryl may be substituted with halogen, CF 3 , C 1 -C 8 -alkyloxy or C 1 -C 4 -alkyl;

A is a single bond, COn, SOn or CONH;

n is 1 or 2;

R 7 is hydrogen;

or C1-C18-alkenyl, which can be mono- to tri-substituted with a substituent from the series consisting of C1-C4-alkyl, halogen, CF3, C1-C4-alkyloxy, N(C1-C4-alkyl)2, -COOH, C1 -C4-alkyloxycarbonyl, C6-C12-aryl, C6-C12-aryloxy, C6-C12-arylcarbonyl, C6-C10-aryl-C1-C4-alkyloxy or oxo, wherein aryl can be substituted with halogen, C1 -C4-alkyl, aminosulfonyl or with methylmercapto;

C6-C10-aryl-C1-C4-alkyl, C5-C8-cycloalkyl-C1-C4-alkyl, C5-C8-cycloalkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl, biphenylyl, diphenyl-C1-C4-alkyl, indanyl, which can be singly or doubly substituted with a substituent from the series consisting of C1-C18-alkyl, C1-C18-alkyloxy, C3-C8-cyclo-alkyl, COOH, hydroxy, C1-C4 -alkylcarbonyl, C6-C10-aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, nitro, cyano, C6-C10-aryl, fluorosulfonyl, C1-C6-alkyloxy -carbonyl, C6-C10-arylsulfonyloxy, pyridyl, NHSO2-C6-C10-aryl, halogen, CF3 or OCF3, wherein the alkyl may be substituted again with C1-C4-alkyloxycarbonyl, CF3 or with carboxy, and the aryl may be substituted with halogen, CF3 or C1-C4-alkyloxy;

or the group Het-(CH2)r-; whereby

r = 0, 1, 2 or 3 and

Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzofused or substituted with a substituent from the series consisting of C1-C4-alkyl, C6-C10-aryl, halogen, C1-C4-alkyloxy, C1-C4-alkyloxycarbonyl, aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkylmercapto or nitro, wherein the benzofused aryl can in turn be substituted with halogen, C1-C4-alkyloxy or CF3 and the alkyl in the arylalkyl can be substituted with methoxy and CF3, as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

The mentioned aryl radicals can be, as necessary, singly or multiply substituted with C1-C9-alkyl, C1-C8-alkyloxy, halogen, trifluoromethyl. The mentioned cycloalkyl radicals can be, as necessary, singly or multiply substituted with C1-C4-alkyl, C6-C10-aryl, and the mentioned alkyl radicals can be substituted with hydroxy, di-C1-C4-alkylamino and with fluorine. Halogen is fluorine, chlorine, bromine, primarily fluorine and chlorine. Alkyl, alkenyl, alkyloxy, etc. may be branched or unbranched.

Preference is given to the use of compounds of formula 1, in which

R 1 is C 1 -C 6 -alkyl, which may be optionally substituted with phenyl; and/or

R 5 is hydrogen; and/or

R2 is hydrogen, halogen, C1-C4-alkyl, C1-C9-alkyloxy or amino,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

Preference is also given to the use of compounds of formula 1, in which

R3 is hydrogen, C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, which can be substituted in the aryl part with halogen if necessary, or NR6-A-R7, where

R6 = hydrogen or benzyl,

A = single bond i

R7 = C6-C10-aryl-C1-C4-alkyl, which may be substituted with halogen, CF3, cyano, phenyl-C1-C4-alkyloxy, CF3-phenoxy, C5-C8-cycloalkyl or fluorosulfonyloxy;

C1-C12-alkyl, which may be substituted with C1-C4-alkyloxy, phenyl, CF3 or with phenyl-C1-C4-alkyloxy;

C2-C12-alkenyl or the group Het-(CH2)r-; where

r = 0 or 1, i

Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzocondensed and substituted with C1-C4-alkyl or halogen, or compounds of formula 1, in which

R2 and R3 independently of each other represent hydrogen, C6-C10-aryl, C3-C8-cycloalkyl, optionally substituted with C1-C4-alkyl, C6-C10-aryloxymethyl, optionally substituted with C1-C4-alkyl or singly or multiply substituted with halogen O-benzyl, O-C6-C10-aryl or O-C3-C8-cycloalkyl, mono- or multi-substituted with fluorine, C6-C10-aryl or amino-substituted O-C1-C6-alkyl, wherein the amino on its part can be singly or multiply substituted with C1-C4-alkyl, SO2-NH-C1-C6-alkyl, as necessary with N(C1-C6-alkyl)2 substituted SO2-NH-(2,2,6,6-tetramethylpiperidine- 4-yl), SO2-NH-C3-C8-cycloalkyl substituted with C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or CO-N(C1-C6-alkyl)2, and N(C1 -C6-alkyl)2 can also be piperidino, morpholino or piperazino, which can be substituted with C1-C4-alkyl if necessary,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

In addition, preference is given to the use of compounds of formula 1 in which

R4 is hydrogen, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-C10-aryl-C1-C4-alkyloxy, may be substituted with halogen, and/or

compounds of formula 1, in which

R4 = NR6-A-R7, where

R6= hydrogen or methyl,

A = single bond i

R7 = hydrogen;

C1-C12-alkyl, which may be singly or doubly substituted with halogen;

C2-C12-alkenyl, which may be singly or doubly substituted with C1-C4-alkyl or C1-C4-alkyloxycarbonyl;

C6-C10-aryl-C1-C4-alkyl, which may be substituted with halogen, C1-C6-alkyloxy, CF3, cyano, C5-C6-cycloalkyl, C1-C4-alkyloxycarbonyl, C6-C10-aryl-C1-C4 -alkyl, C6-C10-aryl-C1-C4-alkyloxy, wherein the aryl can be substituted once more with halogen or CF3;

C5-C8-cycloalkyl-C1-C4-alkyl;

or the group Het-(CH2)r-, where

r = 1, 2 or 3 and

Het = saturated or unsaturated 5-7-membered heterocycle, which can be substituted with halogen, C1-C4-alkyloxy or with C1-C4-alkyloxycarbonyl,

and/or compounds of formula 1, in which

R4 = NR6-A-R7, where

R6 = hydrogen,

A = -CO- i

R7= C1-C10-alkyl, which can be substituted with halogen, phenyl, phenoxy, phenylcarbonyl or C1-C4-alkyloxycarbonyl, whereby phenoxy can be substituted with methyl, halogen or methylmercapto;

C2-C18-alkenyl, which may be substituted with C6-C10-aryl;

C6-C10-aryl, which may be substituted with halogen, phenyl-C1-C4-alkyl, CF3, OCF3, fluoro-sulfonyl, C1-C4-alkyloxycarbonyl, phenoxy, wherein the aryl in turn may be substituted with C1-C4 -alkyloxy;

C6-C10-aryl-C1-C4-alkyl, wherein alkyl may be substituted with methoxy or CF3, and aryl which may be substituted with halogen; or

group Het-(CH2)r-; where

r = 0 and

Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzofused and substituted with C1-C4-alkyl, halogen, C1-C4-alkyloxy, halogen-phenyl or halogen-benzyl-mercapto, whereby the benzofused aryl on its part may be substituted with halogen or methoxy, and/or compounds of formula 1, in which

R4 = NR6-A-R7, where

R6 = hydrogen, A = -CO2- and

R7 = C1-C18-alkyl, which may be substituted with or phenyl;

C6-C10-aryl;

C6-C10-aryl-C1-C4-alkyl, which may be substituted with C1-C4-alkyl, halogen, CF3 or OCF3, benzyloxy or phenyl; or

group Het-(CH2)r-; where

r = 0 or 1 and

Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzofused and substituted with C1-C4 or benzyl, and/or

R4 = NR6-A-R7, where

R6 = hydrogen,

A = -SO2- i

R7 = C1-C6-alkyl, which may be substituted with C2-C4-alkenyl, which may be substituted with phenyl;

C6-C10-aryl, which may be substituted with C1-C6-alkyl, halogen, C1-C4-alkyloxy or benzyl;

biphenylyl-C1-C4-alkyl, substituted with halogen; or

group Het-(CH2)r-, where

r = 0 and

Het = saturated or unsaturated 5-7 membered heterocycle, and/or

compounds of formula 1 in which

R4 = NR6-A-R7, where

R6 = hydrogen,

A = -CO-NH- and

R7 = C1-C10-alkyl, which can be substituted with C1-C4-alkyloxycarbonyl, N(C1-C4-alkyl)2 or phenyl, which in turn can be substituted with halogen or with aminosulfonyl;

C6-C10-aryl, which may be substituted with C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkyloxycarbonyl, phenoxy, OCF3, benzyl. or pyridyl, wherein the alkyl may be substituted once again by C1-C4-alkyloxycarbonyl or by carboxy;

C5-C8-cycloalkyl, which may be substituted with hydroxy, or indanyl; or

group Het-(CH2)r-; where

r = 0 or 1 and

Het = saturated or unsaturated 5-7-membered heterocycle, which can be substituted with benzyl,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

Preference is further given to the use of compounds of formula 1, in which

R2 and R5 represent hydrogen,

R3 is hydrogen, C6-C10-aryl, O-C6-C10-aryl, optionally substituted with C1-C4-alkyl, C6-C10-aryloxymethyl, O-benzyl, singly or multiply with fluorine or amino-substituted O-C1-C6 -alkyl, whereby amino can be mono- or multi-substituted with C1-C4-alkyl, as necessary with C1-C4-alkyl mono- or multi-substituted O-C3-C8-cycloalkyl and

R4 is hydrogen, C6-C10-aryl, C3-C8-cycloalkyl, optionally with C1-C4-alkyl or with halogen mono- or multiply substituted O-C6-C10-aryl or O-C3-C8-cyclo-alkyl, mono or multiply fluorine-substituted O-C1-C6-alkyl, SO2-NH-C1-C6-alkyl, optionally substituted with N(C1-C6-alkyl)2, SO2-NH-(2,2,6,6- tetramethyl-piperidin-4-yl), SO2-NH-C3-C8-cycloalkyl, singly or multiply substituted with C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or CO-N(C1-C6- alkyl)2, i

N(C1-C6-alkyl)2, and also piperidino, morpholino or piperazino, which can be substituted with C1-C4-alkyl if necessary,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

Particular preference is given, furthermore, to the use of compounds of formula 1, in which

R 1 represents methyl, ethyl, butyl, isopropyl or benzyl, and

R 2 and R 5 represent hydrogen, and

R3 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethyl-cyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylamino-ethyloxy or 3-methylphenoxy-methyl, and

R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexyl-aminosulfonyl, 2,2,6,6,-tetramethyl- piperidin-4-yl-aminosulfonyl, 2-(diiso-propylaminoethyl)amino-sulfonyl, 4-methyl-piperazin-1-yl-sulfonyl, 3,3,-dimethylpiperidino-carbonyl or 3,5-dichloro-phenoxy,

or compounds of formula 1 in which

R 1 represents methyl, ethyl, butyl, isopropyl or benzyl, and

R 2 and R 5 represent hydrogen, and

R3 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethyl-cyclohexyloxy, benzyloxy or phenoxy and

R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethyl-cyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholino-sulfonyl or 3,3,5-trimethylcyclohexyl-aminosulfonyl,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

A very special advantage is the use of compounds of formula 1, in which

R1 is C1-C4-alkyl,

R2 is hydrogen,

R3 is hydrogen, trifluoromethoxy, benzyloxy,

R4 is hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoylamino, and

R5 is hydrogen,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

Furthermore, the use of compounds of formula 1, in which

R1 represents methyl,

as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase.

In addition, the use of the compounds of formula I listed in examples 86, 210, 212, 213, 216, 218, 220 and 229 is of particular advantage.

The invention relates to the use of compounds of formula I in the form of their racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and their mixtures.

Pharmaceutically acceptable salts are especially suitable for medical use due to their better solubility in water compared to the starting or basic compounds. These salts must contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I are salts of inorganic acids, such as hydrochloric, hydrobromic, phosphoric, meta-phosphoric, nitric, sulfonic and sulfuric acids, as well as organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. Chloride salt and tartaric acid salt are especially advantageously used for medicinal purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium calcium salts).

Salts with non-pharmaceutically acceptable anions also fall within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example in vitro, applications.

The term "physiologically functional derivative", as used herein, means any physiologically tolerable derivative of a compound according to the invention, eg an ester, which given to a mammal, such as a human, can (directly or indirectly) give such compound or its active metabolites.

A further aspect of this invention is the use of prodrugs of the compounds of formula 1. Such prodrugs can be metabolized in vivo to the compound of formula 1. These prodrugs may or may not be effective.

The compounds of formula I can also exist in different polymorphic forms, eg as amorphous and crystalline polymorphic forms. All polymorphic forms of compounds of formula 1 fall within the scope of the invention and represent a further aspect of the invention.

In the following, each reference to "compound(s) of formula 1" refers to the compound(s) of formula I as described above, as well as to their salts, solvates and physiologically functional derivatives as described herein.

The amount of the compound of formula 1 required to achieve the desired biological effect depends on a number of factors, eg on the specific compound chosen, on the intended use, on the method of administration and on the clinical condition of the patient. Generally, the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg to 50 mg) per day per kilogram of body weight, eg 3-10 mg/kg/day. The intravenous dose may be, for example, in the range of 0.3 mg to 1.0 mg/kg, and as a dose suitable for infusion, 10 ng to 100 ng per kilogram per minute may be given. Suitable infusion solutions for this purpose may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individual doses can contain, for example, from 1 mg to 10 g of active substance. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and formulated unit doses for oral administration, such as for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the above mass data refer to the mass of the salt of the compound of formula I. For the prophylaxis or therapy of the above mentioned conditions, the compounds of formula I can be used in the form of the compound itself as such, however, they are primarily used together with a tolerable carrier in the form of a pharmaceutical preparation. Of course, the carrier must be tolerable in the sense that it is compatible with the other ingredients of the formulation and that it is not harmful to the health of the patient. The carrier may be a solid or a liquid or both and is formulated with the compound preferably as a single dose such as tablets which may contain from 0.05% to 95% by weight. % active substance. Other pharmaceutically active substances may also be present, including other compounds of formula 1.

The pharmaceutical preparations according to the invention can be produced by a known pharmaceutical process, which mainly consists in mixing the ingredients with pharmacologically tolerable carriers and/or auxiliary substances.

The pharmaceutical compositions of the invention are such that they are suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intra-muscular, intradermal or intravenous) administration, although the most suitable route of administration depends in each case on the type and the severity of the condition being treated and the type of compound of formula 1 in question used. Dragee formulations and sustained release dragee formulations also fall within the scope of the invention. Preference is given to formulations that are resistant to gastric acid and gastric juices. Suitable gastric-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

Suitable pharmaceutical compounds for oral administration can be in separate units such as for example capsules, host capsules, lozenges or tablets, which in each case contain a certain amount of the compound of formula 1; as a powder or granulate; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. These preparations can be produced, as already mentioned, by any suitable pharmaceutical process, which includes a step in which the active substance is brought into contact with the carrier (which may consist of one or more additional ingredients). In general, preparations are produced by uniformly and homogeneously mixing the active substance with a liquid and/or finely divided solid carrier, after which, if necessary, the product is shaped. Thus, tablets can be produced, for example, by compressing or molding a powder or granulate of the compound, optionally together with one or more additional ingredients. Pressed tablets can be produced in a suitable machine by tableting the compound in a free-flowing form, such as for example a powder or granulate, which is optionally mixed with a binder, a glidant, an inert developer and/or one or more surfactants. or dispersants. Molded tablets can be produced on a suitable machine by pressing a powdered compound moistened with an inert liquid diluent.

Pharmaceutical preparations suitable for oral (suplingual) administration include lozenges containing the compound of formula I together with a flavoring agent, usually sucrose and gum arabic, or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin, or sucrose and gum arabic.

Suitable pharmaceutical formulations for parenteral administration preferably include sterile aqueous preparations of the compound of formula I, which are preferably isotonic with the recipient's blood. These preparations are preferably given intravenously, although they can also be given by injection subcutaneously, intramuscularly or intradermally. These preparations can be produced primarily by mixing the compound with water and the resulting solution is sterilized and made isotonic with blood. Formulations according to the invention that can be given by injection generally contain from 0/1 to 5 wt. % of active compound.

Suitable pharmaceutical formulations for rectal administration are preferably in the form of suppositories for individual doses. They can be produced by mixing a compound of formula I with one of several common solid carriers, for example cocoa butter, and molding the resulting mixture in a mold.

Suitable pharmaceutical formulations for topical application to the skin are usually in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Vaseline, lanolin, polyethylene glycol, alcohols and combinations of two or more such substances can be used as carriers. The active substance is generally present in a concentration of 0.1 to 15 wt. % of the formulation, for example from 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceutical formulations for transdermal applications may be in the form of individual patches suitable for long-term close contact with the patient's epidermis. Such patches preferably contain an active substance in, if necessary, a buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable concentration of the active substance is approx. 1% to 35%, preferably approx. 3% to 15%. As a specific possibility, the active substance can be released by electrotransport or iontophoresis, as described for example in Pharmaceutical Research, 2(6): 318 (1986).

The following preparations serve to explain the invention, but it is not limited to them.

Example A

Gelatin soft capsules containing 100 mg of active substance each

1 capsule contains:

active substance 100 mg

mixture of triglycerides fractionated from coconut fat 400 mg

capsule content 500 mg

Example B

Emulsion containing 60 mg of active substance in 5 ml

100 ml of emulsion contains:

active substance 1.2 g

neutral oil q. with.

sodium carboxymethylcellulose 0.6 g

polyoxyethylene stearate q. with.

pure glycerin 0.2 to 2.0 g

flavoring substance q. with.

water (desalted or distilled) ad 100 ml

Example C

Rectal form of the drug containing 40 mg of active substance per suppository

1 suppository contains:

active substance 40 mg

base mass for suppositories ad 2 g

Example D

Tablets containing 40 mg of active substance per tablet

1 tablet contains:

active substance 40 mg

lactose 600 mg

corn starch 300 mg

soluble starch 20 mg

magnesium stearate 40 mg

1000 mg

Example E

Dragees containing 50 mg of active substance per dragee

1 dragee contains

active substance 50 mg

corn starch 100 mg

lactose 60 mg

sec. calcium phosphate 30 mg

soluble starch 5 mg

magnesium stearate 10 mg

colloidal silicic acid 5 mg

260 mg

Example F

The following recipes are suitable for producing the contents of hard gelatin capsules:

a) active substance 100 mg

corn starch 300 mg

400 mg

b) active substance 140 mg

milk sugar 180 mg

corn starch 180 mg

500 mg

Example G

Drops can be produced according to the following recipe:

(100 mg of active substance in 1 ml = 20 drops):

active substance 10 g

benzoic acid methyl ester 0.07 g

benzoic acid ethyl ester 0.03 g

ethanol 96% 5 ml

demineralized water ad 100 ml

The production of compounds of general formula 1 can be carried out by known methods in different ways.

[image]

For example, substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-one of general formula 1 can be produced by reacting hydrazine of general formula 2 with chloroformic acid esters of formula 3 or with other reactive carbonic acid ester derivatives, in wherein R1, R2, R3, R4 and R5 are defined as above, thereby obtaining compounds of formula 4, which are acylated with phosgene, carbonyldiimidazole, digosgene or triphosgene, and cyclized and, if necessary, converted into compounds of formula 1 by further chemical modifications of the radical R3 -R5, as for example by reduction of the nitro group to amino radicals by known methods, and then by acylation or alkylation.

As acids are usually released in these reactions, it is recommended to add bases such as pyridine, triethylamine, sodium lye or alkaline carbonates to speed them up. The reactions can be carried out in wide temperature ranges. As a rule, it is advantageous to work at 0°C up to the boiling point of the solvent used. For example, methylene chloride, THF, DMF, toluene, acetic ester, heptane, dioxane, diethyl ether can be used as solvents.

Hydrazines of formula 2 can be obtained by known methods, for example by diazotizing the corresponding anilines

[image]

and then by reduction by known methods or by nucleophilic substitution of appropriately substituted phenyl derivatives 6 (X = F, Cl, Br, I, OS02CF3) with hydrazine hydrate. Such suitable phenyl derivatives can be nitro-substituted halobenzenes, preferably fluoro- and chloro-nitrobenzenes, from which compounds of formula I can be obtained in the appropriate stage of synthesis by reduction and reaction with acylating or alkylating agents, such as, for example, acid chlorides, anhydrides , isocyanates, chloroformic acid esters, sulfonic acid chlorides or alkyl- and arylalkyl-halides, or by reductive alkylation with aldehydes according to known methods.

The following examples further explain the preparation procedures, but do not limit them.

Examples

Example 1

3-methyl-4-nitro-phenylhydrazine

In a solution of 15.9 g of 2-methyl-4-fluoro-nitrobenzene in 10 ml of N-methylpyrrolidone, 5 g of hydrazine hydrate is added dropwise, slowly and at room temperature, and the mixture is heated for 4 hours at 65°C with stirring. The product is precipitated by adding 70 ml of water, suction and recrystallized from isopropanol. Yield: 13.3 g. Melting point: 138°C.

The following examples were obtained by an analogous procedure:

Example 2

3-fluoro-4-nitro-phenylhydrazine

Melting point: 130°C.

Example 3

2-chloro-4-nitro-phenylhydrazine

Melting point: 144°C.

Example 4

2-methyl-4-nitro-phenylhydrazine

Melting point: 135°C.

Example 5

3-(4-Fluorobenzyloxy)-2-nitro-phenylhydrazine

Melting point: 164°C.

The starting compound, 2-fluoro-4-(4-fluorobenzyloxy)-nitro-benzene (melting point: 99°C) was obtained by alkylation of 3-fluoro-4-nitrophenol with 4-fluorobenzyl chloride in DMF in the presence of potassium carbonate.

Example 6

3-(4-fluorobenzyloxy)-4-nitro-phenylhydrazine (intermediate product)

Melting point: 145°C.

Example 7

4-(4-Chlorophenoxy)-3-nitro-aniline

1.4 g of potassium carbonate is added to a solution of 1.29 g of 4-chlorophenol in 8 ml of DMF and after stirring for 30 minutes, 1.6 g of 4-fluoro-3-nitro-aniline is added and the mixture is stirred for 3 hours at 100°C. When it cools down, add 80 ml of water and after brief mixing, the precipitate is sucked off and dried in a vacuum at 40°C. Yield: 2.0 g; melting point: 101°C.

Example 8

4-(4-Chlorophenoxy)-3-nitro-phenylhydrazine

In a mixture consisting of 1.9 g of 4-(4-chloro-phenoxy)-3-nitro-aniline, 25 ml conc. of hydrochloric acid and 25 ml of ethanol, cooled to 0°C, a solution of 0.52 g of sodium nitrite in 5 ml of water is added dropwise and the mixture is stirred for another 60 minutes at -0°C, and then added dropwise to a suspension of 8.5 g of tin dichloride dihydrate in 8 ml conc. HCl. The precipitate is suctioned off, washed with water, mixed under nitrogen in 200 ml of water and dissolved with 100 ml of 30% sodium hydroxide solution at 10-15°C. The resulting oil is shaken with ethyl acetate, washed with water, and the organic phase is dried with sodium sulfate. The product is then precipitated with isopropanol HCl, filtered off with suction and dried in vacuo. Yield: 1.1 g; melting point: 221°C.

Example 9

N'-(4-nitro-2-methyl-phenyl)-hydrazino-formic acid methyl ester

Into the mixture consisting of 0.84 g of 2-methyl-4-nitro-phenylhydrazine, 15 ml of NMP and 2 ml of pyridine, 0.43 ml of chloroformic acid methyl ester is carefully added dropwise while cooling, and then slowly heated to stir at room temperature for 2 hours. It is diluted with 50 ml of water and then the mixture is stirred overnight. The solid is dried in a vacuum at 40°C. Yield: 0.81 g; melting point: 153°C.

The following examples were produced in a similar manner.

Example 10

N'-(4-nitro-phenyl)-hydrazino-formic acid methyl ester (intermediate product)

Melting point: 179°C.

Example 11

N'-(3-fluoro-4-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 127.4°C.

Example 12

N'-(3-methyl-4-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 159°C.

Example 13

N'-(2-chloro-4-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 156°C.

Example 14

N'-(3-(4-fluorobenzyloxy)-4-nitro-phenyl)-hydrazino-formic acid methyl ester (intermediate product)

Melting point: 166°C.

Example 15

N'-(3-(4-fluorobenzyloxy)-2-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 193°C.

Example 16

N'-(4-(4-chlorophenoxy)-3-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 147°C.

Example 17

N'-(3-piperidino-4-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 131°C.

This compound and the compound from example 18 were obtained by the reaction of N'-(3-fluoro-4-nitro-phenyl)-hydrazino-formic acid methyl ester with piperidine or N-benzyl-piperazine in NMP at 80°C.

Example 18

N'-(3-(N-benzyl-piperazino)-4-nitro-phenyl)-hydrazino-formic acid methyl ester

Melting point: 156°C.

Example 19

5-methoxy-3-(4-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

2.5 g of N'-(4-nitro-phenyl)-hydrazino-formic acid methyl ester and 5 ml of pyridine are placed in 15 ml of methylene chloride and mixed with 3 ml of a 20% solution of phosgene while stirring and cooling with ice. in toluene. This mixture is allowed to stand overnight at room temperature and is diluted with a further 10 ral of methylene chloride and then washed 3 times with water. After drying over sodium sulfate, the mixture is concentrated in a vacuum and the product is purified by column chromatography (silica gel, solvent: methanol:methylene chloride = 2:98) and recrystallized from isopropanol. Yield: 1.5 g; melting point: 151°C.

The following examples were obtained analogously to example 4.

Example 20

5-methoxy-3-(3-methyl-4-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 112°C.

Example 21

5-methoxy-3-(4-(4~chlorophenoxy-3-nitro-phenyl)-3-H-(1,3,4)-oxadiazol-2-one

Melting point: oil.

Example 22

5-methoxy-3-(3-(4-fluorobenzyloxy)-2-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 99°C.

Example 23

5-methoxy-3-(2-methyl-4-nitro-phenyl)-3-H-(1,3,4) oxdiazol-2-one

Melting point: 111°C.

Example 24

5-methoxy-3-(3-(4-fluorobenzyloxy)-4-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 137°C.

Example 25

5-methoxy-3-(4-amino-phenyl)-3-H-(1,3,4) oxdiazol-2-one

The mixture consisting of 1.4 g of 5-methoxy-3-(4-nitro-phenyl)-3-H-(1,3,4)oxdiazol-2one, 0.5 g of Pd/C and 20 ml of methanol is hydrogenated is under normal pressure at room temperature until the calculated amount of hydrogen is consumed. Then the catalyst is filtered off and the solution is concentrated in vacuo. The remaining semi-solid substance is mixed with isopropanol and suction. Yield: 0.75 g; melting point: 85°C.

Example 26

5-methoxy-3-(2-amino-4-(4-fluorobenzyloxy}-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: oil.

Example 27

5-methoxy-3-(3-amino-4-(4-chlorophenoxy)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 133°C.

Example 28

5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 114°C.

Example 29

5-Methoxy-3-(4-amino-3-(4-fluorobenzyloxy)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 195°C.

Example 30

5-methoxy-3-(4-(4-chlorophenylacetylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

To an ice-cold mixture consisting of 200 mg of 5-methoxy-3-(4-amino-phenyl)-3-H-(1,3,4)oxadiazol-2-one, 20 ml of methylene chloride and 0.1 ml of pyridine, 201 mg of 4-chlorophenylacetic acid chloride is added dropwise and the reaction mixture is stirred for 5 hours at room temperature. The volatile part is removed in vacuo and the residue is mixed with water and the solid is sucked off and dried at 40°C in vacuum. Yield: 318 mg; melting point: 161°C.

The following examples were obtained by an analogous procedure.

Example 31

5-methoxy-3-(4-(4-chlorophenylacetylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 190°C.

Example 32

5-methoxy-3-(4-octanoylamino-3-methyl-phenyl)-3-H-(1,3,4)-oxadiazol-2-one

Melting point: 110°C.

Example 33

5-methoxy-3-(4-(4-heptyl-benzoylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 155°C.

Example 34

5-methoxy-3-(4-(4-butyl-phenyl-sulfonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 135°C.

Example 35

5-raethoxy-3-(4-(4-chlorobutanoylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 137°C.

Example 36

5-methoxy-3-(4-pivaloylamino-3-methyl-phenyl)-3-H-(1,3,4)-oxadiazol-2-one

Melting point: 157°C.

Example 37

5-methoxy-3-(4-(4-chlorophenylsulfonylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 147°C.

Example 38

5-methoxy-3-(4-(1-naphthylsulfonylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 123°C.

Example 39

5-methoxy-3-(4-(2-phenylethenylsulfonylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 129°C.

Example 40

5-methoxy-3-(4-(2,2,2-trifluoroethyl-sulfonylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 151°C.

Example 41

5-methoxy-3-(4-(benzyloxycarbonylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 115°C.

Example 42

5-methoxy-3-(4-(3,4-dichlorophenylamino-carbonylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 210°C.

This compound was obtained by the reaction of 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with an equimolar amount of 3,4-dichlorophenylisocyanate in toluene at 50°C.

Example 43

5-methoxy-3-(4-(4-chlorophenylsulfonylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 169°C.

Example 44

5-methoxy-3-(4-(2-chlorophenylsulfonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 171°C.

Example 45

5-methoxy-3-(4-(3-chlorophenylsulfonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 141°C.

Example 46

5-methoxy-3-(4-(4-chlorophenylacetyl-amino)-3-(4-fluorobenzyl-oxy)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 167°C.

Example 47

5-methoxy-3-(4-benzylsulfonylamino-phenyl)-3-H-(1,3,4)-oxadiazol-2-one

Melting point: 153°C.

Example 48

5-Methoxy-3-(4-(-2-(4'-chloro-biphenyl)-ethyl)-sulfonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 165°C.

Example 49

5-Methoxy-3-(4-isopropylsulfonylamino-phenyl)-3-H-(1,3,4)-oxdiazol-2-one

Melting point: 190°C.

Example 50

5-methoxy-3-(4-dimethylamino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 71°C

This compound was obtained by reacting 5-methoxy~3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one with paraformaldehyde, formic acid in DMF at room temperature temperature and was purified by column chromatography (silica gel, acetic ester-heptane = 1:1).

Example 51

5-methoxy-3-(4-(4-chlorobenzylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: oil.

This compound was obtained by reacting 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one with 4-chlorobenz-aldehyde/sodium borohydride in methanol /methylene chloride at room temperature and was purified by column chromatography (silica gel, acetate:n-heptane = 1:1).

Example 52

5-Methoxy-3-(4-(2-oxo-pyrrolidin-1-yl)-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: oil.

This compound was obtained by reacting 5-methoxy-3-(4-(4-chloro-butanoylamino)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one with sodium hydride in dioxane at room temperature and purification of the crude product by column chromatography (silica gel/methylene chloride:methanol = 98:2).

Example 53

5-Methoxy-3-(4-(4-oxo-pent-2-en-2-yl-amino)-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 143°C

This compound was obtained by the reaction of 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with an equimolar amount of acetylacetone in glacial acetic acid at 80° C and precipitation with the addition of water and is isolated by filtration.

Example 54

5-Methoxy-3-(4-(2,5-dimethyl-pyrrol-1-yl)-3-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one Melting point: oil.

This compound was obtained by the reaction of 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with an equimolar amount of acetylacetone in glacial acetic acid at 80° C. Processing was carried out by working up with water, shaking with acetic ester and column chromatography (silica gel, methylene chloride) of the dried organic phase after concentrating the obtained crude product.

Example 55

5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-methylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one Melting point: 98°C.

This compound was obtained as a side product during the hydrogenation of 5-methoxy-3-(3-(4-fluorobenzyloxy)-4-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one with platinum dioxide as a catalyst in methanol at room temperature under normal pressure and after removal of the catalyst by filtration, concentration of the reaction mixture and column chromatography (silica gel, methylene chloride).

The compounds of examples 56-199 were obtained analogously to the previous examples.

Example 56

5-methoxy-3-(3-amino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 95°C.

Example 57

5-methoxy-3-(3-dibenzylamino-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 71°C.

Example 58

5-methoxy-3-(3-benzylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: oil.

Example 59

5-Methoxy-3-(4-(pyrid-2-yl)-amino-carbonyl-amino-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 81°C.

Example 60

5-methoxy-3-(3-(4-fluorobenzyl-oxy)-4-benzyloxycarbonyl-amino-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: oil.

Example 61

5-methoxy-3-(4-amino-2-methyl-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: oil.

Example 62

5-methoxy-3-(3-methyl-4-(2-chlorobenzyloxycarbonylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 161°C.

Example 63

5-methoxy-3-(4-amino-2-chloro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 126°C.

Example 64

5-methoxy-3-(2-chloro-4-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 92°C.

Example 65

5-methoxy-3-(2-methyl-4-benzyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 112°C.

Example 66

5-methoxy-3-(2-methyl-4-(4-trifluoromethoxybenzoylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 150°C.

Example 67

5-methoxy-3-(2-chloro-4-benzyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 150°C.

Example 68

5-methoxy-3-(3-fluoro-4-nitro-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 127°C.

Example 69

5-methoxy-3-(4-(4-t-butyl-benzoylamino)-phenyl)-3-H-(1,3,4)-oxadiazol-2-one

Melting point: 173°C.

Example 70

5-methoxy-3-(4-(4-chloro-benzyloxycarbonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 177°C.

Example 71

5-Methoxy-3-(2-chloro-4-(4-heptylbenzoylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 135°C.

Example 72

5-methoxy-3-(4-(3,4-dichlorobenzoylamino)-phenyl)-3-H-(1,3,4)-oxadiazol-2-one

Melting point: 200°C.

Example 73

5-methoxy-3-(4-(2-(4-chlorophenoxy)-2-methyl-propionylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 153°C.

Example 74

5-ethoxy-3-(3-methyl-4-benzyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 94°C.

Example 75

5-isopropoxy-3-(3-methyl-4-benzyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 119°C.

Example 76

5-isopropoxy-3-(3-methyl-4-butyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 114°C.

Example 77

5-isopropoxy-3-(3-methyl-4-(3-chlorophenylamino-carbonyl-amino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 201°C.

Example 78

5-tert-butoxy-3-(3-methyl-4-benzyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 113°C.

Example 79

5-Methoxy-3-(3-methyl-4-phenoxycarbonylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 145°C.

Example 80

5-methoxy-3-(3-methyl-4-(pyrid-3-yl-carbonylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: oil.

Example 81

5-Methoxy-3-(3-methyl-4-(indan-2-yl-aminocarbonylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 206°C.

Example 82

5-methoxy-3-(3-methyl-4-(pyrid-3-yl-methylaminocarbonyl-amino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 229°C.

Example 83

5-Methoxy-3-(3-methyl-4-(pyrid-3-yl-methoxycarbonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 232°C.

Example 84

5-methoxy-3-(3-fluoro-4-benzyloxycarbonylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: oil.

Example 85

5-methoxy-3-(3-fluoro-4-(4-trifluoromethylbenzoylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: oil.

Example 86

5-methoxy-3-(3-benzyloxy-4-(4-trifluoromethylbenzoylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 159°C.

Example 87

5-methoxy-3-(3-fluoro-4-(4-tert-butyl-benzoylamino)-phenyl)-3-H-(1,3,4)oxdiazol-2-one

Melting point: 144°C.

Example 88

5-methoxy-3-(3-methyl-4-(2,2,2-trifluoroethoxycarbonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 141°C.

Example 89

5-Methoxy-3-(3-methyl-4-piperidinocarbonylamino-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 154°C.

Example 90

5-methoxy-3-(4-(6-methoxy-benzofuran-2-yl-carbonylamino)-phenyl)-3-H-(1,3,4)oxadiazol-2-one

Melting point: 191°C.

Further examples were obtained by the procedure described above and were characterized by mass spectroscopy (M+1):

Prim. Chemical symbol M+1 Molecule

no. mass

91 N-[4-(5-methoxy-2-oxo-[1,3,4]-ox-diazol-3-yl)-phenyl]-3-methylbenzene-sulfonamide 362 361.4

92 3,4-dimethoxy-N-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-benzenesulfonamide 408 407.4

93 quinoline-8-sulfonic acid-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-amide 399 398.4

94 N-[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-5-nitro-isophthalic acid

monomethyl ester 415 414.3

95 3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid-[4-(5-methoxy-2-oxo-[1,3,4]

oxdiazol-3-yl)-phenyl]-amide 427 426.8

96 3,3,3-trifluoro-2-methoxy-N-[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-2

-phenyl-propionamide 424 423.3

97 2-fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-benzamide 330 329.3

98 tetradecanoic acid [4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-amide 418 417.5

99 N-[4-(5-raethoxy-2-oxo[1,3,4]ox-diazol-3-yl)-phenyl]-2-phenethyl-benzamide 416 415.4

100 N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-2-(4-methoxy-phenoxy)-5-nitro-

benzamide 479 478.4

101 2-(4-benzyloxy-phenyl)-N-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl[]-acetamide 432 431.4

102 N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-3,3,3-triphenyl-propionamide 492 491.5

103 N-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-3,5-bis-trifluoro-methyl-benzamide 448 447.3

104 4-cyano-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazoI-3-yl)-phenyl-benzamide 337 336.3

105 nonanoic acid [4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-amide 348 347.4

106 9-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenylcarbamoyl]-nonanoic acid

methyl ester 406 405.4

107 undecanoic acid-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)phenyl]-amide 376 375.5

108 4-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)phenylcarbamoyl]benzenesulfonylfluoride 394 393.3

109 11-phenoxy-undecanoic acid-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)phenyl]amide 468 467.6

110 N-[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-2,3-diphenyl-propionamide 416 415.4

111 4-chloro-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-2-methyl-benzamide 360 359.8

112 6-chloro-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-nicotinamide 347 346.7

113 5-fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-2-methyl-benzamide 344 343.3

114 N-[4-{5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-2,4,6-trimethyl-benzamide 354 353.4

115 N-[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-3-naphthalen-2-yl-acrylamide 388 387.4

116 5-oxo-5-phenyl-pentanoic acid-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]

-amide 382 381.4

117 3-{2,4-dichloro-benzylsulfanyl)-thiophene-2-carboxylic acid [4-(5-methoxy-2-oxo

-[1,3,4]oxdiazol-3-yl)-phenyl]-amide 509 508.4

118 2-fluoro-N-[4-(5-methoxy-2-oxo-[1,3,43oxdiazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide 398 397.3

119 1-hexyl-3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 335 334.4

120 1-(4-bromo-phenyl)-3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 406 405.2

121 1-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-3-(2-methoxy-phenyl)-urea 357 356.3

122 2-[3-[3-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-ureido]-3-phenyl-propion

acid ethyl ester 427 426.4

123 1-(2,6-diisopropyl-phenyl)-3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 411 410.5

124 1-[3-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-3-octyl-urea 363 362.4

125 1-(4-fluoro-benzyl)-3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 359 358.3

126 1-(2-ethyl-phenyl)-3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl}-phenyl]-urea 355 354.4

127 6-[3-[3-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-ureido]-hexanoic acid

ethyl ester 393 392.4

128 1-(2,6-dimethoxy-phenyl)-3-[3-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-urea 387 386.4

129 5-methoxy-3-[4-[(thiophen-3-ylmethyl)-amino]-phenyl]-3H-[1,3,4]oxdiazol-2-one 304 303.3

130 4-[[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenylamino]-methyl]-benzonitrile

-trifluoroacetate 437 436.3

131 3-[4-(2-bromo-4,5-dimethoxy-benzylamino)-phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-one 437 436.3

132 3-[4-(3-ethoxy-4-methoxy-benzyl-amino)-phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-one

-trifluoroacetate 486 485.4

133 4-[[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenylamino]-methyl]-benzoic acid

methyl ester trifluoroacetate 470 469.4

134 acetic acid-4-[[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenylamino]-methyl]-phenyl

ester 356 355.3

135 5-methoxy-3-[4-(pentafluorophenyl-methyl-amino)-phenyl]-3H-[1,3,4]oxadiazol-2-one 388 387.3

136 3-[4-(4-benzyloxy-benzylamino)-phenyl]-5-methoxy-3H-[1,3,4]ox-diazol-2-one

-trifluoroacetate 518 517.5

137 3-[4-(3,3-dichloro-nonylamino)-phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 517 516.3

138 2-[[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenylamino]-methyl]-benzonitrile 323 322.3

139 3-[4-(cyclohexylmethyl-amino)phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-one 304 303.4

140 5-methoxy-3-[4-(2,3,5-trichlorobenzyl-amino)phenyl]-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 515 514.7

141 3-[4-(5-bromo-2-fluoro-benzylamino)-phenyl]-5-methoxy-3H-[1,3,4]ox-diazo1-2-one

-trifluoroacetate 509 508.2

142 3-[4-(4-hexyloxy-benzylamino)-phenyl]-5-methoxy-3H-[1,3,4]ox-diazol-2-one

-trifluoroacetate 512 511.5

143 5-methoxy-3-[4-[3-(3-trifluoromethyl-phenoxy)-benzylamino]-phenyl]-3H-[1,3,4]

oxdiazol-2-one-trifluoroacetate 572 571.4

144 3-[4-[(2-chloro-quinolin-3-ylmethyl)-amino]-phenyl] 5-methoxy-3H-[1,3,4]oxdiazol-2-one

-trifluoroacetate 497 496.8

145 3-methoxy-5-[[4-(5-raethoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenylamino]-methyl]pyridin-2

-carbonic acid 501 500.4

146 benzenesulfonic acid-4-[[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenylamino]

-methyl]-phenyl ester 454 453.5

147 2-(2,6-dimethyl-4-methylsulfanyl-phenoxy)-N-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)

-phenyl]-acetamide 416 415.5

148 1-(2,4-difluoro-phenyl)-3-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-urea 363 362.3

149 1-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-3-(4-phenoxy-phenyl)-urea 419 418.4

150 1-(2,6-difluoro-phenyl)-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-y])-phenyl]-urea 363 362.3

151 1-butyl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 307 306.3

152 1-(2-ethoxy-phenyl)-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazo]-3-yl)-phenyl]-urea 371 370.4

153 1-(2,6-dibromo-4-fluorophenyl)-3-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-urea 503 502.1

154 1-(4-butoxy~phenyl)-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 399 398.4

155 1-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-3-(4-trifluoro-methoxy-phenyl)-urea 411 410.3

156 1-benzyl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 341 340.3

157 1-(3-fluoro-phenyl)-3-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-urea 345 344.3

158 6-[3-[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]ureido]-hexanoic acid ethyl

ester 393 392.4

159 1-biphenyl-4-yl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-urea 403 402.4

160 2-[3-[4-(5-methoxy-2-oxo-[1,3,4]-oxdiazol-3-yl)-phenyl]-ureido]-benzoic acid

butyl ester 427 426.4

161 5-methoxy-3-[3-(7-methoxy-3,7-dimethyl-octylamino)-phenyl]-3H-[1,3,4]oxadiazol-2-one

-trifluoroacetate 492 491.5

162 5-methoxy-3-[3-[(thiophen-2-ylmethyl)-amino]-phenyl]-3H-[1,3,4]oxdiazol-2-one

-trifluoroacetate 418 417.4

163 3-(3-hexylamino-phenyl)-5-methoxy-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 406 405.4

164 5-methoxy-3-[3-(3-phenyl-propyl-amino)-phenyl]-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 440 439.4

165 5-methoxy-3-(3-undecylamino-phenyl)-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 476 475.5

166 5-methoxy-3-[3-[3-(3-trifluoromethyl-phenoxy)-benzylamino]-phenyl]-3H-[1,3,4]oxdiazole

-2-one-trifluoroacetate 572 571.4

167 3-[3-[(2-chloro-quinolin-3-ylmethyl)-amino]-phenyl]-5-methoxy-3H-[1,3,4]oxdiazol-2

-one-trifluoroacetate 497 496.8

168 4-fluoro-benzenesulfonic acid-4-[[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)

phenylamino]-methyl]-phenyl ester-trifluoroacetate 586 585.5

169 5-methoxy-3-[3-(3,4,5-trifluoro-benzylamino)-phenyl]-3H-[1,3,4]oxdiazol-2-one

-trifluoroacetate 466 465.3

170 3-[3-(3,5-bis-trifluoromethyl-benzyl-amino)-phenyl]-5-methoxy-3H-[1,3,4]-oxadiazol-2-one

-trifluoroacetate 548 547.3

171 3-(3-dec-4-enylamino-phenyl)-5-methoxy-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 460 459.5

172 3-[3-(3-cyclopentyl-2-phenethyloxy-benzylamino)-phenyl]-5-methoxy-3H-[1,3,4]oxdiazole-2

-one-trifluoroacetate 600 599.6

173 4-[[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenylamino]-methyl]-benzonitrile

-trifluoroacetate 437 436.3

174 5-methoxy-3-[3-[(6-methyl-pyridin-2-ylmethyl)-amino]-phenyl]-3H-[1,3,4]oxadiazol-2-one

-trifluoroacetate 427 426.3

175 3-[3-(2-benzyloxy-ethylamino)-phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 456 455.4

176 3-[3-(2,6-difluoro-benzylamino)-phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-one-trifluoroacetate 448 447.3

Melting point [ºC]

177 dodecanoic acid [4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-amide 93

178 octadec-9-enoic acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-phenyl]-amide 67

179 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid 2-methoxy-ethyl ester 117

180 1-(4-hydroxy-cyclohexyl)-3-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-y])-2-methyl-phenyl]-urea 220

181 1,1-dibutyl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-urea oil

182 5-Methoxy-benzofuran-2-carboxylic acid-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)

-2-methyl-phenyl]-amide 199

183 4-methyl-piperazine-1-carboxylic acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl

-phenyl]-amide oil

184 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid-1-methyl

-piperidin-4-yl ester 235

185 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazo]-3-yl)-2-methyl-phenyl]-carbamic acid-cyclohexyl ester 163

186 4-Benzyl-piperidine-1-carboxylic acid-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl}-2-methyl-phenyl]

-amide 146

187 1-(2-diisopropylamino-ethyl)-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-urea 136

188 4-(2-{3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-ureido}-ethyl)-benzenesulfonamide 200

189 1-(1-benzyl-piperidin-4-yl)-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]- urea 198

190 1-(4-isopropyl-phenyl)-3-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-urea 200

191 2-{3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-ureido}-3-methyl-butyric acid 246

192 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid 1,2,3,4

-tetrahydro-naphth-1-yl ester 159

193 [4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid 1-phenyl-ethyl ester oil

194 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid 4-isopropyl-benzyl

ester 88

195 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid

4-trifluoromethoxy-benzyl ester 82

196 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid 3,5-dichloro

-benzyl ester 169

197 [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]-carbamic acid biphenyl-2-ylmethyl

ester 138

198 5-chloro-benzofuran-2-carboxylic acid-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-2-methyl-phenyl]

-amide 210

199 5-chloro-benzofuran-2-carboxylic acid-[4-(5-methoxy-2-oxo[1,3,4]oxdiazol-3-yl)-phenyl]-amide 209

Example 200

4-fluoro-benzenesulfonic acid-morpholide (intermediate product)

20 g of morpholine are added dropwise to an ice-cold solution of 19.5 g of 4-fluoro-benzenesulfonic acid chloride in 100 ml of toluene and the mixture is heated under reflux for 1 hour. When cooled, it is concentrated in vacuo, mixed with water, the precipitate is filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 16.9 g; melting point: 140°C.

Example 201

4-hydrazino-benzenesulfonic acid morpholide (intermediate product)

5 g of 4-fluoro-benzenesulfonic acid-morpholide is dissolved in 15 ml of N-methylpyrrolidone, mixed with 2.5 g of hydrazine hydrate and heated for 1 hour at 100°C. When it has cooled to room temperature, add 75 ml of water and mix at room temperature. After 2 hours, the solid substance is sucked off and recrystallized from isopropanol. Yield: 3.2 g; melting point: 164°C.

The following examples were obtained analogously.

Example 202

4-hydrazino-benzenesulfonic acid-(3,3,5-trimethyl-cyclohexyl)-amide (intermediate product)

Melting point: 129°C.

Example 203

4-(3,3,5,5-tetramethylcyclohexyl-oxy)nitrobenzene (intermediate product)

1.3 g of sodium hydride is added to a solution of 7.8 g of 3,3,5,5-tetramethylcyclohexanol in 50 ml of dimethylformamide and the mixture is stirred for 30 minutes at 40-50°C. Then a total of 7.0 g of 4-fluoro-nitrobenzene is added in portions and the mixture is then heated for 3 hours at 100°C and cooled to room temperature. 250 ml of ice water is added and mixed, the resulting solid is sucked off and dried in a vacuum. Yield: 8.6 g; melting point: 70°C.

Example 204

4-(3,3,5,5-tetramethylcyclohexyl-oxy)-aniline (intermediate product)

8.3 grams of 4-(3,3,5,5-tetramethylcyclohexyloxy)-nitro-benzene is hydrogenated in 500 ml of methanol in the presence of 400 mg of platinum dioxide and under normal pressure until hydrogen bonding ceases. The catalyst is filtered off and the solution is spun off, the residue, which has the form of a brownish oil that gradually solidifies, is used for the next conversion without further purification. Yield: 7.3 g

Example 205

4-(3,3,5,5-tetramethylcyclohexyl-oxy)-phenylhydrazine-hydrochloride (intermediate product)

To the mixed mixture consisting of 3.7 g of 4-(3,3,5,5-tetramethylcyclohexyl-oxy)-aniline, 7.5 ml of water and 15.5 ml of conc. HCl, cooled to -10°C, is added dropwise to a solution of 1.13 g of sodium nitrite in 7.5 ml of water and the mixture is stirred for another 45 minutes at -10°C. This is then added dropwise to a suspension of 9.3 g of tin dichloride dihydrate in 7 ml conc. HCl. The precipitate is suctioned off, washed with water, mixed under nitrogen in 200 ml of water and dissolved with 100 ml of 30% sodium hydroxide solution at 10-15°C. The newly formed precipitate is filtered off with suction, washed with water, taken up in 200 ml of ether and dried with sodium sulfate. The product is then precipitated with ethereal HCl, filtered off with suction and dried under vacuum. Yield: 2.1 g; melting point: 171°C.

Example 206

N'-(4-morpholinosulfonyl-phenyl)-hydrazino-formic acid ethyl ester (intermediate product)

In a mixture consisting of 0.275 g of morpholide 4-hydrazinobenzene-sulfonic acid, 5 ml of methylene chloride and 1 ml of pyridine, 114 mg of ethyl ester of chloroformic acid is carefully added dropwise while cooling with ice and then warmed to room temperature with gentle stirring. It is diluted with 10 ml of water and the product is stirred with acetic ester, the phase in acetic ester is washed several times with water, dried over sodium sulfate and concentrated. The oily crude product thus obtained is further converted without further cleaning. Yield: 0.25 g.

Example 207

3-(4-morpholinosulfonyl-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

The oil from Example 206 is placed in 5 ml of methylene chloride and mixed with 1 ml of a 20% solution of phosgene in toluene with stirring and cooling with ice. This mixture is allowed to stand overnight at room temperature, diluted with a further 10 ml of methylene chloride and then washed 3 times with water. After drying over sodium sulfate, the mixture is concentrated in vacuo and the product is purified by column chromatography (silica gel, solvent: methanol: methylene chloride = 2:98). Yield: 130 mg; melting point: 195°C.

The following examples were obtained analogously to example 207.

Example 208

3-(4-morpholinosulfonyl-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 164°C.

Example 209

3-(4-trifluoromethoxy-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 52°C.

Example 210

3-(4-trifluoromethoxy-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: 63°C.

Example 211

3-(4-trifluoromethoxy-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 212

3-(4-trifluoromethoxy-phenyl)-5-butoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 213

3-(4-trifluoromethoxy-phenyl)-5-benzyloxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 214

3-(4-(3, 3,5-trimethyl-cyclohexyl-amino-sulfonyl)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 164°C.

Example 215

3-(4-(3,3,5,5-tetraethylcyclohexyl-oxy)-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: 111°C.

Example 216

3-(3-benzyloxy-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 217

3-(3-benzyloxy-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: 85°C.

Example 218

3-(3-trifluoromethoxy-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 219

3-(3-trifluoromethoxy-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 220

3-(3-trifluoromethoxy-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 221

3-(4-(2,2,6,6-tetramethyl-piperidin-4-yl-amino-sulfonyl)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Example 222

3-(4-(2,2,6,6-tetramethyl-piperidin-4-yl-amino-sulfonyl)-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Example 223

3-(4-(2-(diisopropylaminoethyl)amino-sulfonyl)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 224

3-(4-(2-(diisopropylaminoethyl)amino-sulfonyl)-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 225

3-(4-(4-methyl-piperazin-1-yl-sulfonyl)-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Example 226

3-(4-(4-methyl-piperazin-1-yl-sulfonyl)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Example 227

3-(3-(4,4,4-trifluoro-butyl-oxy)-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 228

3-(3-(2-diethylamino-ethyl-oxy)-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: resin

Example 229

3-(4-(4-chlorophenoxy)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 68°C.

Example 230

3-(4-(4-chlorophenoxy)-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 231

3-(4-(3,3,5-trimethyl-cyclohexyl-amino-sulfonyl)-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: oil.

Example 232

3-(3-phenoxy-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 89°C.

Example 233

3-(3-phenoxy-phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one

Melting point: 50°C.

Example 234

3-(3-phenoxy-phenyl)-5-isoproxy-1,3,4-oxdiazol-2-one

Melting point: 58°C.

Example 235

3-(4-phenoxy-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 83°C.

Example 236

3-(4-cyclohexyl-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Example 237

3-(3-(3,3,5,5-tetramethyl-cyclohexyl-oxy)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 68°C.

Example 238

3-(4-phenyl-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: >260°C (exp.).

Example 239

3-(3-(3-methylphenoxy-methyl)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 47°C.

Example 240

3-(3-phenyl-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: 80°C.

Example 241

3-(4-(3,3-dimethylpiperidino-carbonyl)-phenyl)-5-methoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Example 242

3-(4-(3,3,5,5-tetramethyl-cyclohexyloxy)-phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one

Melting point: resin.

Compounds of formula 1 show an inhibitory effect on pancreatic lipase (PL). As inhibitors of PL, they can prevent the resorption of fat taken in with food and thus lead to a decrease in fat consumption and body weight or to a decrease in body weight. The compounds of formula I are particularly suitable for the production of drugs for the treatment of obesity and type 1 and type 2 diabetes.

The efficacy of the compounds was determined as follows.

1. Preparation of the substrate

80 μl of tripalmitin (85 mM in chloroform) was mixed with 5 μl of glycerine-tri[9,10(n)-3H]oleate (5 mCi/ml in toluene) in a 12 ml polypropylene container. After rotary evaporation (50°C) and addition of 4 ml of 200 mM Tris/HCl (pH 7.6), 0.8% TX-100, the mixture was sonicated (Branson Sonifier B-12, power level 4.3 times 2 minutes with intervals of 1 minute on ice) until the formation of a homogeneous milky cloudy suspension.

2. Experiment

Lipase buffer: 80 mM Tris/HCl (pH 7.6), 600 mM NaCl, 8 mM CaCl2, 8 mM benzamidine, 2 mM Pefabloc (Roche Biochemicals) (inhibitors were added on the day of the experiment).

Pancreatic lipase: An enriched preparation from porcine pancreas (Sigma, order number L-0382) dissolved in lipase buffer (100000 units/500 μl).

Implementation

5 μl of test substance (in 100% DMSO) or DMSO (control) was mixed with 10 μl of substrate and 5 μl of lipase (in that order) and incubated for 30 minutes at 30°C (Eppendorf Thermomixer, 350 min-1). After addition of 325 μl of methanol/chloroform/n-heptane (10/9/7) and 105 μl of 0.1 M K2CO3, 0.1 M H3BO3 (pH 10.5 adjusted with 1M KOH) and vigorous mixing, it was centrifuged until separation phase (8000 rpm, 4°C, Eppendorf centrifuge). Each 140 μl of the aqueous residue, which contained the released radiolabeled oleate (recollected 70%), was transferred to a 20 ml scintillation dish and mixed with 6 ml of scintillation liquid (Beckman ReadySafe). After vigorous mixing and incubation for 2 h at room temperature, radioactivity was measured on a liquid scintillation counter (Beckman, L8008, tritium channel with extinction curve, measurement time 20 minutes).

Display of results

Substances were routinely tested at each concentration in three separately incubated reaction mixtures, in each case twice, after phase separation (SD < 0.02). Basic, blank values (reaction carried out under the same conditions, but without lipase) were subtracted from all values (corresponding mainly to the proportion of glycerin trioleate, i.e. the proportion of free oleate in the substrate preparation in the aqueous phase, <5% of the radioactivity used). Inhibition of the enzymatic action of pancreatic lipase with the test substance was determined by comparison with an uninhibited control reaction (presence of lipase = 0% inhibition; absence of lipase 100% inhibition in each case after correction of the blank value). The IC50 value was calculated using the inhibition curve with up to 8 concentrations of the test substance. The GRAPHIT software package (Elsevier-BIOSOFT) was used to adjust the curves and determine the IC50 value.

According to this test system, the compounds of formula 1 showed the following effect:

[image]

Claims (17)

1. Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones of the general formula 1, [image] indicated by the fact that in them R1 represents C1-C6-alkyl, C3-C9-cycloalkyl, whereby both groups can be mono- or multi-substituted with phenyl, C1-C4-alkyloxy, S-C1-C4-alkyl, N(C1-C4-alkyl)2 , and phenyl, on the other hand, can be singly or multiply substituted with halogen, C1-C4-alkyl, C1-C4-alkyloxy, nitro, CF3; and R 2 , R 3 , R 4 and R 5 independently represent hydrogen, halogen, nitro, C 1 -C 4 -alkyl; C1-C9-alkyloxy, which is substituted with fluorine, C6-C10-aryl, amino or with C1-C4-alkyl-amino; C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C6-C10-aryloxy-C1-C4-alkyl, C3-C8-cycloalkyl or O-C3-C8-cycloalkyl, which may be mono-, di- or tri-substituted with halogen, CF3, C1-C4-alkyloxy or C1-C4-alkyl; SO2-NH-C1-C6-alkyl, optionally substituted with N(C1-C6-alkyl)2, SO2-NH-(2,2,6,6,-tetramethylpiperidin-4-yl), SO2-NH-C1 -C6-cycloalkyl, if necessary singly or multiply substituted with C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or COX, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, provided that R 2 , R 3 , R 4 and R 5 are not simultaneously hydrogen, and X can be O-C1-C6-alkyl, NH-C1-C6-alkyl, NH-C3-C8-cycloalkyl or N(C1-C6-alkyl)2 and N(C1-C6-alkyl)2 and also pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which may optionally be substituted with C1-C4-alkyl, benzyl, C6-C10-aryl, CO-C1-C4-alkyl, CO-C6-C10-aryl, CO-O-C1 -C4-alkyl, SO2-C1-C4-alkyl or R 6 is hydrogen, C 1 -C 4 -alkyl or C 6 -C 10 -aryl-C 1 -C 4 -alkyl, wherein the aryl may be substituted with halogen, CF 3 , C 1 -C 8 -alkyloxy or C 1 -C 4 -alkyl; A is a single bond, COn, SOn or CONH; n is 1 or 2; R 7 is hydrogen; or C1-C18-alkenyl, which can be mono- to tri-substituted with a substituent from the series consisting of C1-C4-alkyl, halogen, CF3, C1-C4-alkyloxy, N(C1-C4-alkyl)2, -COOH, C1 -C4-alkyloxycarbonyl, C6-C12-aryl, C6-C12-aryloxy, C6-C12-arylcarbonyl, C6-C10-aryl-C1-C4-alkyloxy or oxo, wherein the aryl can be substituted with halogen, C1 -C4-alkyl, aminosulfonyl or with methylmercapto; C6-C10-aryl-C1-C4-alkyl, C5-C8-cycloalkyl-C1-C4-alkyl, C5-C8-cycloalkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl, biphenylyl, diphenyl-C1-C4-alkyl, indanyl, which can be singly or doubly substituted with a substituent from the series consisting of C1-C18-alkyl, C1-C18-alkyloxy, C3-C8-cyclo-alkyl, COOH, hydroxy, C1-C4 -alkylcarbonyl, C6-C10-aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, nitro, cyano, C6-C10-aryl, fluorosulfonyl, C1-C6-alkyloxy -carbonyl, C6-C10-arylsulfonyloxy, pyridyl, NHSO2-C6-C10-aryl, halogen, CF3 or OCF3, wherein the alkyl may be substituted once again with C1-C4-alkyloxycarbonyl, CF3 or with carboxy, and the aryl may be substituted with halogen, CF3 or C1-C4-alkyloxy; or the group Het-(CH2)r-; whereby r = 0, 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzofused or substituted with a substituent from the series consisting of C1-C4-alkyl, C6-C10-aryl, halogen, C1-C4-alkyloxy, C1-C4-alkyloxycarbonyl, aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkylmercapto or nitro, wherein the benzofused aryl can in turn be substituted with halogen, C1-C4-alkyloxy or CF3 and the alkyl in the arylalkyl can be substituted with methoxy and CF3, as well as their pharmacologically tolerable salts and acid addition salts for the production of a drug with an inhibitory effect on pancreatic lipase. 2. Use of compounds of formula 1 according to claim 1, characterized in that in them R 1 is C 1 -C 6 -alkyl, which may be optionally substituted with phenyl; and/or R 5 is hydrogen; and/or R2 is hydrogen, halogen, C1-C4-alkyl, C1-C9-alkyloxy or amino. 3. Use of compounds of formula 1 according to claims 1 to 2, characterized in that in them R3 is hydrogen, C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, which can be substituted in the aryl part with halogen if necessary, or NR6-A-R7, where R6 = hydrogen or benzyl, A = single bond i R7 = C6-C10-aryl-C1-C4-alkyl, which may be substituted with halogen, CF3, cyano, phenyl-C1-C4-alkyloxy, CF3-phenoxy, C5-C8-cycloalkyl or fluorosulfonyloxy; C1-C12-alkyl, which may be substituted with C1-C4-alkyloxy, phenyl, CF3 or with phenyl-C1-C4-alkyloxy; C2-C12-alkenyl or the group Het-(CH2)r-; where r = 0 or 1, i Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzofused and substituted with C1-C4-alkyl or halogen. 4. Use of compounds of formula 1 according to claims 1 to 2, characterized in that in them R2 and R3 independently of each other represent hydrogen, C6-C10-aryl, C3-C8-cycloalkyl, optionally substituted with C1-C4-alkyl, C6-C10-aryloxymethyl, optionally substituted with C1-C4-alkyl or singly or multiply substituted with halogen O-benzyl, O-C6-C10-aryl or O-C3-C8-cycloalkyl, mono- or multi-substituted with fluorine, C6-C10-aryl or amino-substituted O-C1-C6-alkyl, wherein the amino on its part can be singly or multiply substituted with C1-C4-alkyl, SO2-NH-C1-C6-alkyl, as necessary with N(C1-C6-alkyl)2 substituted SO2-NH-(2,2,6,6-tetramethylpiperidine- 4-yl), SO2-NH-C3-C8-cycloalkyl substituted with C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or CO-N(C1-C6-alkyl)2, and N(C1-C6-alkyl)2 can also be piperidino, morpholino or piperazino, which can be substituted with C1-C4-alkyl if necessary, 5. Use of compounds of formula 1 according to claims 1 to 4, characterized in that in them R4 is hydrogen, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-C10-aryl-C1-C4-alkyloxy, may be substituted with halogen. 6. Use of compounds of formula 1 according to claims 1 to 5, characterized in that in them R4 = NR6-A-R7, where R6= hydrogen or methyl, A = single bond i R7= hydrogen; C1-C12-alkyl, which may be singly or doubly substituted with halogen; C2-C18-alkenyl, which may be singly or doubly substituted with C1-C4-alkyl or C1-C4-alkyloxycarbonyl; C6-C10-aryl-C1-C4-alkyl, which may be substituted with halogen, C1-C6-alkyloxy, CF3, cyano, C5-C6-cycloalkyl, C1-C4-alkyloxycarbonyl, C6-C10-aryl-C1-C4 -alkyl, C6-C10-aryl-C1-C4-alkyloxy, wherein the aryl can be substituted once more with halogen or CF3; C5-C8-cycloalkyl-C1-C4-alkyl; or the group Het-(CH2)r-; where r = 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered heterocycle, which can be substituted with halogen, C1-C4-alkyloxy or with C1-C4-alkyloxycarbonyl. 7. Use of compounds of formula 1 according to claims 1 to 6, characterized in that in them R4 = NR6-A-R7, where R6 = hydrogen, A = -CO- i R7= C1-C10-alkyl, which can be substituted with halogen, phenyl, phenoxy, phenylcarbonyl or C1-C4-alkyloxycarbonyl, whereby phenoxy can be substituted with methyl, halogen or methylmercapto; C2-C18-alkenyl, which may be substituted with C6-C10-aryl; C6-C10-aryl, which can be substituted with halogen, C1-C8-alkyl, phenyl-C1-C4-alkyl, CF3, OCF3, fluoro-sulfonyl, C1-C4-alkyloxycarbonyl, phenoxy, while the aryl can be substituted with C1-C4-alkyloxy; C6-C10-aryl-C1-C4-alkyl, wherein alkyl may be substituted with methoxy or CF3, and aryl which may be substituted with halogen; or group Het-(CH2)r-; where r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzofused and substituted with C1-C4-alkyl, halogen, C1-C4-alkyloxy, halogen-phenyl or halogen-benzyl-mercapto, whereby the benzofused aryl on its part may be substituted with halogen or with methoxy. 8. Use of compounds of formula 1 according to claims 1 to 7, characterized in that in them R4 = NR6-A-R7, where R6 = hydrogen, A = -CO2- i R7 = C1-C18-alkyl, which may be substituted with CF3 or phenyl; C6-C10-aryl; C6-C10-aryl-C1-C4-alkyl, which may be substituted with C1-C4-alkyl, halogen, CF3 or OCF3, benzyloxy or phenyl; or group Het-(CH2)r-; where r = 0 or 1 and Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzocondensed and substituted with C1-C4-alkyl or benzyl. 9. Use of compounds of formula 1 according to claims 1 to 8, characterized in that in them R4 = NR6-A-R7, where R6 = hydrogen, A = -SO2- i R7 = C1-C6-alkyl, which may be substituted with CF3; C2-C4-alkenyl, which may be substituted with phenyl; C6-C10-aryl, which may be substituted with C1-C6-alkyl, halogen, C1-C4-alkyloxy or benzyl; biphenylyl-C1-C4-alkyl, substituted with halogen; or group Het-(CH2)r-; where r = 0 and Het = saturated or unsaturated 5-7 membered heterocycle. 10. Use of compounds of formula 1 according to claims 1 to 9, characterized in that in them R4 = NR6-A-R7, where R6 = hydrogen, A = -CO-NH- and R7 = C1-C10-alkyl, which can be substituted with C1-C4-alkyloxycarbonyl, N(C1-C4-alkyl)2 or phenyl, which in turn can be substituted with halogen or with aminosulfonyl; C6-C10-aryl, which may be substituted with C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkyloxycarbonyl, phenoxy, OCF3, benzyl or pyridyl, wherein the alkyl may be further substituted with C1-C4- alkyloxycarbonyl or with carboxy; C5-C8-cycloalkyl, which may be substituted with hydroxy, or indanyl; or group Het-(CH2)r-; where r = 0 or 1 and Het = saturated or unsaturated 5-7 membered heterocycle, which may be substituted with benzyl. 11. Use of compounds of formula 1 according to claims 1 to 10, characterized in that in them R2 and R5 represent hydrogen, R3 is hydrogen, C6-C10-aryl, O-C6-C10-aryl, optionally substituted with C1-C4-alkyl, C6-C10-aryloxymethyl, O-benzyl, singly or multiply with fluorine or amino-substituted O-C1-C6 -alkyl, whereby amino can be mono- or multi-substituted with C1-C4-alkyl, as necessary with C1-C4-alkyl mono- or multi-substituted O-C3-C8-cycloalkyl and R4 is hydrogen, C6-C10-aryl, C3-C8-cycloalkyl, optionally with C1-C4-alkyl or with halogen mono- or multi-substituted O-C6-C10-aryl or O-C3-C8-cycloalkyl, mono- or multi-substituted fluorine-substituted O-C1-C6-alkyl, SO2-NH-C1-C6-alkyl, optionally substituted with N(C1-C6-alkyl)2, SO2-NH-(2,2,6,6-tetramethyl- piperidin-4-yl), SO2-NH-C3-C8-cycloalkyl, singly or multiply substituted with C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or CO-N(C1-C6-alkyl) 2, i N(C1-C6-alkyl)2, and also piperidino, morpholino or piperazino, which can be substituted with C1-C4-alkyl if necessary. 12. Use of compounds of formula 1 according to claims 1 to 11, characterized in that in them R 1 represents methyl, ethyl, butyl, isopropyl or benzyl, and R 2 and R 5 represent hydrogen, and R3 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethyl-cyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylamino-ethyloxy or 3-methylphenoxy-methyl, and R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexyl-aminosulfonyl, 2,2,6,6,-tetramethyl- piperidin-4-yl-aminosulfonyl, 2-(diiso-propylaminoethyl)amino-sulfonyl, 4-methyl-piperazin-1-yl-sulfonyl, 3,3,-dimethylpiperidino-carbonyl or 3,5-dichloro-phenoxy. 13. Use of compounds of formula 1 according to claims 1 to 11, characterized in that in them R1 represents methyl, ethyl, butyl, isopropyl or benzyl, and R2 and R5 represent hydrogen, and R3 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethyl-cyclohexyloxy, benzyloxy or phenoxy and R 4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethyl-cyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexyl-aminosulfonyl. 14. Use of compounds of formula 1 according to claims 1 to 13, characterized in that in them R1 is C1-C4-alkyl, R2 is hydrogen, R3 is hydrogen, trifluoromethoxy, benzyloxy, R4 is hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoylamino, and R5 is hydrogen. 15. Use of compounds of formula 1 according to claims 1 to 14, characterized in that in them R1 represents methyl. 16. Use of compounds of formula 1 according to claims 1 to 15, characterized in that they are used in combination with one or more pancreatic lipase inhibitors for the production of a medicament for prophylaxis or treatment of obesity. 17. Use of compounds of formula 1 according to claims 1 to 15, characterized in that they are used in combination with one or more pancreatic lipase inhibitors for the production of a drug for the prophylaxis or treatment of type 1 or 2 diabetes.